Behavioral inhibition (BI) is a temperamental style characterized by enhanced sensitivity to threat and a tendency to withdraw from novel or unfamiliar stimuli (Fox, et al., 2004;Kagan, et al., 1998), and it has been shown to be a risk factor for the development of psychopathology later in life (Chronis-Tuscano, et al., 2009). The heightened tendency to engage in avoidance behaviors may be a particular risk factor for BI individuals, as avoidance motivation has been theorized to be a core component of multiple forms of psychopathology (Hayes, et al., 1996). Thus, exploring the neural substrates of behavioral inhibition and avoidance motivation can further our understanding of the etiology of psychopathology. Previous research from our laboratory has demonstrated that BI individuals show heightened striatal activation (Guyer, et al., 2006;Bar-Haim, et al., 2009), particularly to aversive stimuli (Helfinstein, et al., in prep). The striatum is involved in integrating emotionally relevant information and using it to initiate goal-directed behavior (Mogenson, et al., 1980). Neuro-imaging work has demonstrated that BOLD response in the striatum to both appetitive and aversive cues follows a Prediction Error (PE) pattern (O<Doherty, et al., 2003;Seymour, et al., 2007). Given the avoidance tendencies seen in BI individuals, and the role of PEs to aversive cues in initiating avoidance behaviors, we hypothesize that the enhanced striatal activation seen in BI individuals follows a PE pattern. Moreover, we hypothesize that enhanced PE-patterned striatal activation is related to increased avoidance of punished stimuli in a learning task To test these hypotheses, the proposed research study will use a two-block probabilistic learning paradigm (modified from Frank, Seeberger, O<Reilly, 2004) to examine PE-modulated striatal BOLD activation in BI individuals and its relation to approach and avoidance behavior. In one learning block, subjects are rewarded for choosing correct stimuli, while in the other subjects are punished for choosing incorrect stimuli. The unexpectedness of reward and punishment will vary trial-by-trial, and this information can be used to identify brain regions where BOLD activation is modulated by PE. We expect that BI individuals will show greater PE-modulated striatal activation to feedback in the punishment block, but not the reward block. At the end of each learning block, subjects will be presented with a test block that measures how well they have learned to approach the most frequently correct stimulus and avoid the most frequently incorrect stimulus. We expect that increased PE-modulated striatal activation in the punishment block will correlate with higher avoidance accuracy in the test block, while increased PE-modulated striatal activation in the reward block will correlate with higher approach accuracy in the test block. [The role of the anterior cingulate cortex, another region of the brain that plays an important role in learning from aversive feedback (Brown &Braver, 2005), will also be examined.]. Results from this work will inform the underlying neural correlates of behavioral inhibition and provide an endophenotype for development of anxiety disorders. PUBLIC HEALTH RELEVANCE: Given the links between behavioral inhibition, avoidance behavior, and psychopathology, it is a valuable contribution to the public health to explore possible neural substrates of these risk factors. By improving our understanding of the neural mechanisms that are related to heightened avoidance motivation and behavioral inhibition, it is possible to begin exploring the development of these risk factors and possible interventions to disrupt trajectories leading to psychopathology.